{60 -acylhydrazino-{62 -phenyl-propionitriles

ABSTRACT

L- Alpha -acylhydrazino- Beta -phenyl-propionitrile compounds useful as intermediates in the production of L- Alpha -hydrazinoBeta -phenyl-propionic acids. Also included are processes for preparing the compounds of this invention by aminating L- Alpha acylamido- Beta -phenyl-propionitrile and processes for hydrolyzing the compounds of this invention to form L- Alpha hydrazino- Beta -phenyl-propionic acid compounds.

United States Patent Sletzinger et al.

[ 51 July 11,1972

[54] a-ACYLHYDRAZINO-B-PHENYL- PROPIONITRILES [72] Inventors: MeyerSletzinger, North Plainfield; Sandor Karady, Elizabeth; Manuel G. Ly,New Brunswick; Seemon ll. Pines, Murray Hill,

all of NJ.

[73] Assignee: Merck 8: Co., Inc., Rahway, NJ.

[22] Filed: Feb. 24, 1970 21 Appl. No.3 13,770

[52] US. Cl ..260/465 D, 260/47l A, 260/519,

260/556 l-I, 260/559 A, 260/559 A, 260/999 [51] Int. Cl ..C07c 101/72,C07c 103/38 [58] Field of Search ..260/465 D [56] References CitedUNITED STATES PATENTS 3,032,581 5/1962 Leonard ..260/465X 3,505,3854/1970 Reinhold etal ..260/465 OTHER PUBLICATIONS Smith Open-ChainNitrogen Compounds, Vol. 11, W. A. Benjamin, Inc., New York, N.Y., I966,pp. 143- 145.

Primary Examiner-Joseph Rebold Assistant Examiner-Dolph H. TorrenceAttorney-Francis l-I. Deef, Harry E. Westlake, Jr. and 1. Louis Wolk[57] ABSTRACT 4 Claims, No Drawingsa-ACYLHYDRAZINO-B-PHENYL-PROPIONITRILES This invention relates to noveland useful chemical compounds and to a process for their preparation.More particularly, it relates to novel compounds which are intermediatesin the preparation of L-a-hydrazino-B-phenyl-alkanoic acids.

It is known in the art that various a-hydrazino-fi-phenyl-alkanoic acidsare useful as decarboxylase inhibitors. It is further known that theD-isomer of these acids is generally inactive and may even beantagonistic to the action of the L- form, thereby reducing its potency.

In the past, it has been the accepted practice to separate stereoisomersby the formation of diastereomeric salts with either optically activebases or acids, depending on the nature of the racemate. However, withthe hydrazino compounds of the present invention, separation iscomplicated by the fact that some diastereomeric salts do not formcrystalline materi als with sufficiently different properties so thatthe diastereomers can be readily crystallized. In'some instances, thediastereomeric salts are oilyor waxy materials which become difficult ifnot impossible to separate by conventional means. Quite obviously, if arelatively simple and inexpensive process could be found which wouldpreferentially produce the desired L-ahydrazino-B-phenyl-alkanoic acids,.it would receive widespread acceptance in the art.

Accordingly, it is an object of this invention to prepare novelintermediate compounds. A further object of this invention is to providea process for the formation of such intermediates. A still furtherobject is to provide a process by which the novel intermediate productsof this invention may be formed into useful final products. Otherobjects will become apparent from the ensuing descriptionof thisinvention.

These objects are accomplished by the present invention which providesthe L form of a compound of theformula:

wherein:

R and R each may be loweralkoxy, phenyloxy, benzyloxy or hydroxy; R ishydrogen or loweralkyl; R is CN CONH wherein R is loweralkyl, or -COOH;and

R is loweralkanoyl or aroyl.

The loweralltoxy" radical signifies an alkoxy grbup containing from oneto about six carbon atoms and the loweralkyl radical signifies an alkylgroup containing from one to about six carbon atoms which can bestraight chained or branched. While in the most preferred compounds ofthis invention R is loweralkanoyl, it is not necessary to limit R tothis class of substituents. R may be any acy radical derived from anorganic acid by the removal of the hydroxyl group. It includes radicalsderived from carboxylic acids, sulfonic acids and the like. Furthermore,R may also include loweralkyl esters.

Ir. the most preferred embodiments of the present invention R and R eachmay be hydroxy or loweralkoxy, R is loweralkyl, R isCN and R is acetyl.

The present invention also provides a process for preparing the L formofa compound of the formula:

which comprises hydrolyzing the L form of a compound of the formula:

wherein R, R,, R R and-R are as previously defined.

The present invention alsoprovides a process for preparing the L fonn ofa compound of the formula:

which comprises aminating the L form of a compound of the formula:

wherein R, R,, R R and R are as previously defined.

In carrying out the amination reaction of this invention, theacylaminonitrile may be treated with a base as for example an alkalimetal hydride such as sodium hydride or potassium hydride or an alkalimetal alkoxide such as potassium t-butoxide,'potassium ethoxide, etc.,to make the alkali metal salt before reacting it with a suitableaminating agent. The aminating agent may be chloramine, methoxyamine,O-arylhydroxylamine such as O-phenylhydroxylamine and 0-( 2,4-dinitrophenyl)hydroxylamine, hydroxylamine-O-sulfonic acid and itsesters or any other suitable aminating agent. In general, the aminationreaction is carried out in a solvent at a temperature ranging from 70 toC. Suitable solvents include water, methanol, ethanol, ethyl acetate,diethyl ether, hexane, chloroform, methylene chloride and the like. In apreferred embodiment of this invention the reaction is carried out withchloramine or methoxyamine at a temperature of from 30 to +100 C. andmore preferably from -15 to +70 C.

After forming the aminated intermediate products .of the presentinvention, they may be hydrolyzed .with aqueous acid or base undermoderate conditions to remove the acyl group. When other substituentgroups such as the 3,4-dimethoxy or 3,4-dibenzyloxy are present in the Rgroup, these can simultaneously be converted to hydroxyl groups undersomewhat more drastic conditions for hydrolysis. Similarly, the variousR groups can be converted to the carboxyl group by varying thehydrolysis conditions. In general, the hydrolysis is carried out at atemperature of from about room temperature to 175 C., preferably 75 toC. When it is desired to simultaneously convert the 3,4-dimethoxy or3,4-dibenzyloxy to, hydroxyl groups along with hydrolysis of the acylradical, it is preferred that a concentrated (preferably fortified)hydrohalic acid such as hydrochloric or hydrobromie acid be used at atemperature of from 100 to 165 C. When such substituents are not presentor it is not desired to convert the substituent groups, much lessdrastic conditions can be used and either an acid or a base in waterwill suffice for hydrolysis.

The following examples are presented to further illustrate theinvention.

EXAMPLE 1 A.L-a-(1-Acetylhydrazino)-a-methyl-B-(3,4-dimethoxyphenyl)-propionitrileSodium hydride (250 mg., 55 percent in mineral oil, 5.2 mmoles) iswashed with hexane and suspended in 6 m1. of DMSO. To this mixture isadded a solution ofL-a-acetamidoa-methyl-B-(3,4-dimethoxyphenyl)propionitrile (1.05 g., 4mmoles) in 10 ml. of DMSO. After the gas evolution subsides (15 minutes)the solution is cooled to 15 C. and a solution of chloramine (4.5mmoles) in 12 ml. of dry ether is added over a period of 2 minutes.After 12 hours of agitation at room temperature, a few drops of aceticacid is added and the mixture is concentrated in vacuo. The resultingsyrup is partitioned between water and chloroform. The organic layer isdried, the solvent removed and the residue is crystallized from ethylacetate and ether to yield crystalline material.

An analytical sample is prepared by recrystallization from methanol,m.p. 121l23 C.

Anal. Calcd. for C H N O z C, 60.63; H, 6.91;N, 15.15.

FoundzC, 60.82;H,7.l;N, 15.21.

B. L-a-Hydrazino-a-methyl-[H3,4-dihydroxyphenyl)propionic acid Asolution of the product from the previous step (150 mg.) in 2.5 ml. ofconcentrated hydrochloric acid is heated in a sealed tube at 120 C. forl- /z hours. The resulting mixture is evaporated to dryness in vacuo andthe product leached out with ethanol. The hydrazino acid is precipitatedby addition of diethylamine to pH 6.4, the mixture filtered and theprecipitate washed with ethanol and dried to yieldL-ahydrazino-a-methyl-B-(3,4-dihydroxyphenyl)-propionic acid.Recrystallization from water containing a small amount of sodiumbisulfite yields the product, m.p. 208 dec., [a],,=- 17.3(C 2, Ch;,OH).

EXAMPLE 2 A.L-a-(1-Acetylhydrazino)-a-ethyl-/3-(3,4-dimethoxyphenyl)-propionitrileSodium hydride (250 mg., 55 percent in mineral oil, 5.2 mmoles) iswashed with hexane and suspended in 6 ml. of DMSO. To this mixture isadded a solution ofL-a-acetamidoa-ethyl-B-(3,4-dimethoxyphenyl)propionitrile (4 mmoles) inml. of DMSO. After the gaS evolution subsides minutes) the solution iscooled to 15 C. and a solution of chloramine (4.5 mmoles) in 12 ml. ofdry ether is added over a period of 2 minutes. After 12 hours ofagitation at room temperature a few drops of acetic acid is added andthe mixture is concentrated in vacuo. The resulting syrup is partitionedbetween water and chloroform. The organic layer is dried, the solventremoved and the residue is crystallized from ethylacetate and ether toyield crystalline material.

B. L-a-Ethyl-a-hydrazino-/3-(3,4-dihydroxyphenyl)propionic acid Asolution of the product from the previous step in 2.5 ml. ofconcentrated hydrochloric acid is heated in the sealed tube at 120 C.for 1-12 hours. Using the procedure of Example 18, the hydrazino acid isobtained.

EXAMPLE 3 A. L-a-( 1-Acetylhydrazino)-a-methyl-B-( 3-hydroxy-4-methoxyphenyl)-propionitrile To a solution ofL-a-acetamido-a-methyl-B-(3-hydroxy-4- methoxyphenyl)propionitrile (4mmoles) in 10 ml. of DMSO is added 8 mmoles of potassium t-butoxide.After 15 minutes the solution is cooled to 15 C. and a solution ofchloramine (4.5 mmoles) in 12 ml. of dry ether is added over a periodof2 minutes. After 12 hours of agitation at room temperature a few dropsof acetic acid is added and the mixture is concentrated in vacuo. Theresulting syrup is partitioned between water and chloroform. The organiclayer is dried, the solvent removed and the residue is crystallized fromethylacetate and ether to yield crystalline material.

B. L-a-Hydrazino-a-methyl-B-( 3 ,4-dihydroxyphenyl propionic acid Asolution of the product from the previous step in 2.5 ml. ofconcentrated hydrochloric acid is heated in the sealed tube at 120 C.for l-% hours. Utilizing the procedure of Example 18, the hydrazino acidis obtained.

EXAMPLE 4 A. L-a-( 1-Acetylhydrazino)-a-methyl-B-(3,4-dihydroxyphenyl)-propionitrile Potassium hydride (13 mmoles, 55percent in mineral oil) is washed with hexane and suspended in 6 ml. ofDMSO. To this mixture is added a solution of L-a-acetamido-a-methyl-B B-(3,4-dihydroxyphenyl)propionitrile (4 mmoles) in 10 ml. of DMSO. Afterthe gas evolution subsides (15 minutes) the solution is cooled to 15 C.and a solution of 0-24- dinitrophenylhydroxylamine (4.5 mmoles) in 12ml. of dry dioxane is added over a period of 2 minutes. After 12 hoursof agitation at room temperature a few drops of acetic acid is added andthe mixture is concentrated in vacuo. The resulting syrup is partitionedbetween dilute NaOH solution and ether. The organic layer is dried, thesolvent removed and the residue is crystallized from ethylacetate andether to yield crystalline material.

B. L-a-Hydrazino-a-methyl-B-(3,4-dihydroxyphenyl)propionic acid Asolution of the product from the previous step in 2.5 ml. ofconcentrated hydrochloric acid is heated to reflux for 1-% hours.Utilizing the procedure of Example 18, the hydrazino acid is obtained.

EXAMPLE 5 A. L-a-Hydrazino-a-methyl-B-(3,4-dimethoxyphenyl)propionicacid To an ice cold solution of L-a-amino-a-methyl-B-(3,4-dimethoxyphenyl)propionic acid hydrochloride (2.2 g., 8 mmoles) in 2.5 Nsodium hydroxide is added 1.8 g. (16 mmoles) of hydroxylamine-O-sulfonicacid. After 10 minutes, the mixture is heated at C. for 1 hour. Thesolution is acidified with hydrochloric acid and evaporated to drynessin vacuo. The residue is digested with ethanol and the crude productprecipitated by addition of diethylamine to pH 6.5. The mixture ispurified by chromatography After recrystallization from waterL-a-hydrazino-a-methyl-[H3,4-dimethoxyphenyl)propionic acid is obtained,m.p. 222-224 C. dec.

Anal. Calcd. for C, H N O 'H,O: C, 52.93; H, 7.40; N,

Found: C, 53.01; H, 7.46; N, 10.28.

B. L-a-Hydrazino-a-methyl-B-(3,4-dihydroxyphenyl)propionic acid Amixture of L-a-(3,4-dimethoxybenzyl)-a-hydrazinopropionic acid (10.0 g.,32.2 mmoles) and 150 ml. of concentrated hydrochloric acid is heated ina sealed tube at C. for 2 hours. The resulting mixture is evaporated todryness in vacuo and the product leached out with ethanol. The hydrazinoacid is precipitated by addition of diethylamine to pH 6.4, the mixturefiltered and the precipitate washed with ethanol and dried to yieldL-a-hydrazino-a-methyl-B-(3,4- dihydroxyphenyl)propionic acid.Recrystallization from water containing a small amount of sodiumbisulfite yields the product, m.p. 208 C. dec. [0:],,=-17.3C. (C 2, CHOH).

Anal. Calcd. for C, H N,O -H,O: C, 49.17; H, 6.60; N,

11.47. Found: C, 49.13; H, 6.74; N, 11.19.

EXAMPLE 6 A.L-a-(1-benzoylhydrazino)-a-methyl-B-(3,4-dibenzyloxyphenyl)propionamideSodium hydride (250 mg., 55 percent in mineral oil, 5.2 mmoles) iswashed with hexane and suspended in 6 ml. of DMSO. To this mixture isadded a solution ofL-a-benzamidoa-methyl-B-(3,4-dibenzyloxyphenyl)propionamide (4 mmoles)in 10 ml. of DMSO. After the gas evolution subsides (15 minutes) thesolution is cooled at 15 C. and a solution of chloramine (4.5 mmoles) in12 ml. of dry ether is added over a period of 2 minutes. After 12 hoursof agitation at room temperature a few drops of acetic acid is added andthe mixture is concentrated in vacuo. The resulting syrup is partitionedbetween water and chloroform. The organic layer is dried, the solventremoved and the residue is crystallized from ethylacetate and ether toyield crystalline material.

B. L-a-Hydrazino-a-methyl-B-( 3,4-dihydroxyphenyl)propionic acid Asolution of the product from the previous step in 2.5 ml. ofconcentrated hydrochloric acid is heated in the sealed tube at 100 C.for 1- /2 hours. Utilizing the procedure of Example 1B, the hydrazinoacid is obtained.

EXAMPLE 7 A. L-wAcethydrazino-a-ethyl-B-(3,4-dibenzyloxyphenyl)-propionitrile Sodium hydride (250 mg., 55 percent in mineral oil, 5.2mmoles) is washed with hexane and suspended in 6 ml. of DMSO. To asolution of L-a-acetamido-a-ethyl-B-(3,4-dibenzyl-oxyphenyl)propionitrile (4 mmoles) in ml. of DMSO is added 5mmoles of sodium methoxide. After minutes the solution is cooled to 15C. and a solution of chloramine (4.5 mmoles) in 12 ml. of dry ether isadded over a period of 2 minutes. After 12 hours of agitation at roomtemperature a few drops of acetic acid is added and the mixture isconcentrated in vacuo. The resulting syrup is partitioned between waterand chloroform. The organic layer is dried, the solvent removed and theresidue is crystallized from ethylacetate and ether to yield crystallinematerial.

B. L-a-Hydrazino-a-ethyl-B-(3,4-dihydroxyphenyl)propionic acid Asolution of the product from the previous step in 2.5 ml. ofconcentrated hydrochloric acid is heated in the sealed tube at 120 C.for 1- /4. hours. Utilizing the procedure of Example 1 B, the hydrazinoacid is obtained.

EXAMPLE 8 A. L-a'( 1 -Acetylhydrazino )-a-methyl-B-( 3 ,4-dimethoxyphenyl)-propionitrile Sodium hydride (250 mg., 55 percent, in mineraloil, 5.2 mmoles) is washed with hexane and suspended in 6 ml. of DMSO.To this mixture is added a solution ofL-a-acetamidoa-methyl-fi-(3,4-dimethoxyphenyl)propionitrile (4 mmoles)in 10 ml. of DMSO. After the gas evolution subsides (15 minutes) thesolution is cooled to 15 C. and a solution of methoxyamine (4.5 mmoles)in 12 ml. of dry ether is added over a period of 2 minutes. After 12hours of agitation at room temperature a few drops of acetic acid isadded and the mixture is concentrated in vacuo. The resulting syrup ispartitioned between water and chloroform. The organic layer is dried,the solvent removed and the residue is crystallized from ethyl acetateand ether to yield crystalline material.

B. La-Hydrazino-a-methyl-B-(3,4-dihydroxyphen- EXAMPLE9 A. L-a-(1-Acetylhydrazino)-a-ethyl-B-( 3-hydroxy-4-methoxy-phenyl)-N,N-dimethylpropionamide To a solution ofL-u-acetamidou-ethyl-B-(3hydroxy-4-methoxyphenyl)-N,N-dimethylpropionamidc (0.1 mole) in dioxane ml.) isadded potassium t-butoxide ((0.12 moles). After stirring the mixture atroom temperature or 1 hour, O-phenylhydroxylamine (0.12 mole) is added.The mixture is heated at 50 C. for 1 hour and poured on water, extractedwith chloroform, dried, and evaporated to yieldL-al-acetylhydrazino)-a-ethyl-B-(3-hydroxy-4-methoxyphenyl)-N,N-dimethylpropionamide.

B. L-a-Ethyl-a-hydrazino-B-(3,4-dihydroxyphenyl)propionic acid Asolution of the product from the previous step in 2.5 ml. ofconcentrated hydrochloric acid is heated in the sealed tube at C. forl-% hours. Utilizing the procedure of Example 1B, the hydrazino acid isobtained.

What is claimed is:

l. A compound of the formula:

wherein:

R and R, each may be loweralkoxy, phenyloxy, benzyloxy or hydroxy;

R is hydrogen or loweralkyl;

R is CN; and

R is loweralkanoyl.

2. A compound as in claim 1 wherein R and R, are loweralkoxy, R isloweralkyl, R is -CN and R is acetyl.

3. A compound as in claim 1 wherein R is hydroxy, R, is loweralkoxy, Ris loweralkyl, R is -CN and R is acetyl.

4. A compound as in claim 1 wherein R and R, are hydroxy, R isloweralkyl, R is --CN and R, is acetyl.

2. A compound as in claim 1 wherein R and R1 are loweralkoxy, R2 isloweralkyl, R3 is -CN and R4 is acetyl.
 3. A compound as in claim 1wherein R is hydroxy, R1 is loweralkoxy, R2 is loweralkyl, R3 is -CN andR4 is acetyl.
 4. A compound as in claim 1 wherein R and R1 are hydroxy,R2 is loweralkyl, R3 is -CN and R4 is acetyl.